Nonsteroidal Anti-inflammatory Drugs in Dentistry: Implications of the VIOXX Withdrawal

WRITTEN BY
Patricia L. Blanton, DDS, MS, PhD, and Arthur H. Jeske, DMD, PhD

Modern nonsteroidal anti-inflammatory agents (NSAIDs) (e.g., ibuprofen) were introduced in the U.S. pharmaceutical market in the 1970s, and currently are considered the drugs-of-choice in dentistry for the treatment of mild-to-moderate dental pain.1 The recent introduction of celecoxib (Celebrex) and other COX-2 selective inhibitors in the late 1990s was significant, because they afforded beneficial effects in patients with osteoarthritis (theoretically an action associated with inhibition of inflammatory prostaglandins synthesized by the COX-2 enzyme) without the adverse effects of inhibition of “physiologic” prostaglandins that play a role in regulation of normal body functions (synthesized by the COX-1 enzyme).2

The therapeutic actions of NSAIDs include:

* Analgesic

* Anti-inflammatory

• Antipyretic (reduction of elevated body temperature)

On the downside, NSAIDs, particularly nonspecific agents such as ibuprofen and naproxen, are associated with adverse effects, the most significant of which include:

• Gastrointestinal irritation and bleeding

• Inhibition of platelet aggregation

• Allergy (including cross-allergenicity with aspirin in some cases)

• Renal and hepatic dysfunction

• Adverse effects on the developing fetus

Drugs available in the non-COX-2 selective categories are shown in Table 1.

NSAIDs possess advantages over opioids and opioid combination products in that they do not produce drowsiness and sedation, are not controlled substances (they do not produce tolerance and dependence), they are available over-the-counter in reduced-dose formulations, and they typically produce longer-lasting, higher levels of pain relief than opioid/aspirin and opioid/acetaminophen combination products.2 Ibuprofen is available with 7.5 mg hydrocodone (Vicoprofen) for management of moderate levels of dental pain, and now a new Schedule II combination product (Combunox) is available. This agent, for moderately severe and severe levels of pain, contains 5 mg of oxycodone with 400 mg ibuprofen.3

COX-2 selective agents

In patients who cannot take aspirin or NSAIDs, 600 to 900 mg of acetaminophen alone or in combination with hydrocodone (e.g., Vicodin) is appropriate (the maximum daily dose in an adult should not exceed 4,000 mg) for moderate pain.

The COX-2-selective NSAIDs (e.g., celcoxib, Celebrex) have been demonstrated to produce an analgesia equivalent to that produced by the earlier generation of nonselective, propionic acid NSAIDs (e.g., ibuprofen), but with fewer adverse gastrointestinal side effects and fewer problems with platelet aggregation during longer-term (>30 days) treatment.4 However, long-term adverse cardiovascular effects resulted in the withdrawal of rofecoxib (Vioxx) and initiated intensive review by the Food and Drug Administration (FDA, 2003). At this time, it appears that COX-2-selective inhibitors may continue to remain on the market, albeit with stronger precautions and label directions to tailor therapy specifically to individual cases where the drugs may be indicated such as patients with a history of GI bleeding. Following the withdrawal by Merck of Vioxx in September 2004, the FDA continued an intensive reevaluation of the data regarding adverse effects of this class of drugs. As of now, the FDA has offered the following advice in a “talk paper” on COX-2-selective inhibitors:5

✦ Practitioners prescribing Celebrex or Bextra should consider the emerging information on COX-2 inhibitors when determining the relative risks and benefits of such drugs in patients. Patients who may be candidates to receive such drugs include those who are at a high risk of GI bleeding, those who have a prior history of intolerance to NSAIDs generally, or those who are not doing well on nonselective agents.

✦ An individual patient’s risk for adverse cardiovascular events and other adverse effects of NSAIDs should be taken into account for each prescribing situation.

✦The FDA advises consumers that all over-the-counter analgesics, including NSAIDs, should be used in strict accordance with the label directions. Consumers are further advised that if use of an over-the-counter NSAID is needed for longer than 10 days, a physician should be consulted. The FDA also noted that naproxen (e.g., Aleve, Naprosyn) may be associated with an increased risk of adverse cardiovascular events, based on preliminary results from one long-term trial.

Recently, Khan and Dionne reviewed the application of COX-2-selective NSAIDs in dentistry.2 Because COX-2 selectivity is dose-dependent, and because some COX-2-related prostaglandins may play important roles in the normal physiologic regulation of some tissues, COX-2 inhibitors may not avoid all NSAID-related adverse effects. A singular advantage of these drugs pre-operatively may be a lack of effect on platelet aggregation, but when weighed against their cost, they may not represent a significant advantage in dentistry over nonselective NSAIDs.

Furthermore, a review of the efficacy and duration of the COX-2-selective agents reveals that the currently available agents are not more efficacious than conventional nonselective NSAIDs (e.g., ibuprofen, naproxen) for the management of postsurgical dental pain.6 Furthermore, the potential for adverse GI effects for nonselective agents in dentistry is minimized by the relatively short (two to three days) duration that analgesics are usually required postoperatively. In fact, the nonselective agents that have been in use for more than two decades have always proven to be efficacious inhibitors of the pro-inflammatory COX-2 isoenzyme. While their inhibition of the COX-1 cyclooxygenase enzyme does result in significant side effects when taken long term, short-term use tends to minimize these effects.

References

1 Phero J, Becker D. Rational use of analgesic combinations. Dent. Clin. N. Am. 2002; 46:691-705.

2 Khan AA, Dionne RA. The COX-2 inhibitors: New analgesic and anti-inflammatory drugs. Dent Clin N Am 2002; 46:679-690.

3 Product monograph, (Forest Laboratories, www.combunox.com).

4 Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000; 343:1520-8.

5 http://www.fda.gov/bbs/topics/ANSWERS/ 2004/ANS01336.html

6 Jeske AH. Selecting new drugs for pain control: evidence-based decisions or clinical impression? JADA 2002; 133:1052-56. ■

Patricia L. Blanton, DDS, MS, PhD
Dr. Blanton is professor emeritus of anatomy at Baylor College of Dentistry, TAMUS, and is in private practice, specializing in periodontics, in Dallas. She is the current president of the Texas Dental Association. You may contact her at [email protected].

Arthur H. Jeske, DMD, PhD
Dr. Jeske is a professor and chair in the Department of Restorative Dentistry & Biomaterials at the University of Texas Dental Branch, Houston.